Evidence that phosphorylated ubiquitin signaling is involved in the etiology of Parkinson's disease

• Published in: Human molecular genetics 2017-08, Vol.26 (16), p.3172-3185
• Main Authors: Shiba-Fukushima, Kahori, Ishikawa, Kei-Ichi, Inoshita, Tsuyoshi, Izawa, Nana, Takanashi, Masashi, Sato, Shigeto, Onodera, Osamu, Akamatsu, Wado, Okano, Hideyuki, Imai, Yuzuru, Hattori, Nobutaka
• Format: Article
• Language: English
• Subjects: Animals; Brain - metabolism; Dopaminergic Neurons - metabolism; Drosophila - metabolism; Drosophila Proteins - metabolism; Enzyme Activation; HeLa Cells; Humans; Membrane Potential, Mitochondrial; Mitochondria - metabolism; Parkinson Disease - etiology; Parkinson Disease - genetics; Phosphorylation; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Transport; Signal Transduction; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddx201

The ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase Parkin, two gene products associated with young-onset Parkinson's disease (PD), participate in mitochondrial quality control. The phosphorylation of mitochondrial polyUb by PINK1, which is activated in a mitochondrial membrane potential (ΔΨm)-dependent manner, facilitates the mitochondrial translocation and concomitant enzymatic activation of Parkin, leading to the clearance of phospho-polyUb-tagged mitochondria via mitophagy. Thus, Ub phosphorylation is a key event in PINK1-Parkin-mediated mitophagy. Here, we examined the role of phospho-Ub signaling in the pathogenesis of PD using fly PD models, human brain tissue and dopaminergic neurons derived from induced pluripotent stem cells (iPSCs) containing Parkin or PINK1 mutations, as well as normal controls. We report that phospho-Ub signaling is highly conserved between humans and Drosophila, and that phospho-Ub signaling and the relocation of axonal mitochondria upon ΔΨm reduction are indeed compromised in human dopaminergic neurons containing Parkin or PINK1 mutations. Moreover, phospho-Ub signaling is prominent in tyrosine hydroxylase-positive neurons compared with tyrosine hydroxylase-negative neurons, suggesting that PINK1-Parkin signaling is more required for dopaminergic neurons. These results shed light on the particular vulnerability of dopaminergic neurons to mitochondrial stress.